Nutri-stress, mitochondrial dysfunction, and insulin resistance-role of heat shock proteins

Abstract

Excess nutrient flux into the cellular energy system results in a scenario of cellular metabolic stress in diseases involving insulin resistance, such as type 2 diabetes, referred to as nutri-stress and results in cellular bioenergetic imbalance, which leads to insulin resistance and disease. Under nutri-stress, the heat shock response system is compromised due to metabolic abnormalities that disturb energy homeostasis. Heat shock proteins (HSPs) are the chief protectors of intracellular homeostasis during stress. Heat shock response (HSR) impairment contributes to several metabolic pathways that aggravate chronic hyperglycaemia and insulin resistance, highlighting a central role in disease pathogenesis. This article discusses the role of nutri-stress-related molecular events in causing insulin resistance and the nature of the roles played by heat shock proteins in some of the crucial checkpoints of the molecular networks involved in insulin resistance. Ample evidence suggests that the heat shock machinery regulates critical pathways in mitochondrial function and energy metabolism and that cellular energy status highly influences it. Weakening of HSPs, therefore, leads to loss of their vital cytoprotective functions, propagating nutri-stress in the system. Further research into the mechanistic roles of HSPs in metabolic homeostasis will help widen our understanding of lifestyle diseases, their onset, and complications. These inducible proteins may be crucial to attenuating lifestyle risk factors and disease management.

Keywords: Heat shock protein; Insulin resistance; Metabolic flexibility; Mitochondrial dysfunction; Oxidative stress; Sirtuin.

Fig. 1

Outline of the onset of insulin resistance in ageing and lifestyle disease

Fig. 2

Interactions of vital metabolic pathways that lead to insulin resistance in nutri-stress. Nutrient excess due to external lifestyle factors leads to metabolic inflexibility and dysregulation of the bioenergetic chemical signals, i.e. NAD/NADH ratio and AMP/ATP ratio. The onset of oxidative stress occurring parallel to excess oxidation in mitochondria, along with the decreased NAD and increased ATP, jointly involves in the dysregulation of the heat shock response. The blue-coloured portions represent the canonical HSP expression pathway; the grey-coloured represents the oxidative stress-associated pro-inflammatory NF-kB pathway and their interactions with the insulin signalling cascade (green portion) and HSP pathway. GSK-3beta is also included for its role in oxidative stress and HSP repression

Fig. 3

Role of heat shock proteins in nutri-stress. Cellular energetic signals, mainly AMP/ATP ratio and NAD/NADH ratio, are involved in regulating heat shock protein expression. The interplay between SIRT1, AMPK, HSP, and PGC-1α is central to the regulation of cellular energy status. HSP participates via its chaperone function by stabilising mitochondrial structural and functional integrity. It also helps suppress the activity of the NF-kB-associated pro-inflammatory pathway molecules. It directly suppresses the activation of IKKβ and JNK. However, the oxidative stress pathways in chronic stress diminish the HSP function by enabling the activation of GSK3β, which has known inhibitory roles towards HSP72 and HSF-1